Selenium, now recognized as an essential nutrient, is associated with a wide variety of toxic syndromes involving both states of deficiency and excess of this element. Selenium can also inhibit hepatic microsomal drug metabolism in the rat. This project is concerned with investigating this inhibitory effect of selenium on this enzyme system. Initial studies are directed toward characterizing this effect in terms of threshold dose and time course for effect. The nature of the inhibitory action will be assessed by determining the effect of selenium on the apparent kinetic constants, Km and Vmax, for the substrates, ethylmorphine and aniline. Other studies are directed at assessing the interaction of selenium with the biochemical components of the hepatic drug metabolizing system: cytochromes P-450 and b5 and NADPH cytochrome c reductase. Studies will also be undertaken to assess the effects of various parameters which may alter the ability of cadmium to inhibit drug metabolism such as: decreased heptic glutathione levels; treatment with phenobarbital, SKF-525A, or ethionine; or the effect of selenium in female rats. A chronic feeding study will be undertaken to determine the sensitivity of this enzyme system to dietary selenium. Studies will also be conducted to assess the protective role of selenium in ameliorating cadmium toxicity, using as our model the ability of cadmium to inhibit hepatic drug metabolism in the rat.